TRANSIENT IMMUNOSUPPRESSION PERMITS SUCCESSFUL REPETITIVE INTRAVENOUSADMINISTRATION OF AN ADENOVIRUS VECTOR

The in vivo administration of adenovirus vectors frequently elicits a neutralizing antibody response which eliminates or substantially reduc es the efficacy of subsequent treatments. Methods to overcome this sig nificant barrier to repeat delivery will be required for the applicati on of adenovirus-based gene therapy in the treatment of chronic diseas e; We have evaluated the relationship between the initial vector dose and the effectiveness of a second vector administration. C57BL/6 mice injected intravenously with up to 10(7) p.f.u. of a lacZ adenovirus ve ctor, Av1lacZ4, expressed significant levels of human factor IX when i njected with 2x10(8) p.f.u. of the factor IX vector, Av1H9F, 5 weeks l ater. An initial dose of 10(8) p.f.u. of Av1lacZ4 completely prevented expression of factor IX following the second administration due to th e generation of neutralizing antibody. However, transient immunosuppre ssion with deoxyspergualin (DSG) or cyclophosphamide at the time of in itial exposure to 10(8) p.f.u. of Av1lacZ4 prevented the formation of anti-adenovirus neutralizing antibody and permitted an effective secon d administration of a factor IX vector. Furthermore, transient immunos uppression with cyclophosphamide concomitant with delivery of the fact or IX vector enabled an effective administration of a third vector enc oding human factor VIII. This approach, together with strategies to pr olong the persistence of adenoviral vector expression, should permit l ong-term therapy with adenovirus-based vectors.